Abstract

Human gut microbiome composition is shaped by multiple factors but the relative contribution of host genetics remains elusive. Here we examine genotype and microbiome data from 1,046 healthy individuals with several distinct ancestral origins who share a relatively common environment, and demonstrate that the gut microbiome is not significantly associated with genetic ancestry, and that host genetics have a minor role in determining microbiome composition. We show that, by contrast, there are significant similarities in the compositions of the microbiomes of genetically unrelated individuals who share a household, and that over 20% of the inter-person microbiome variability is associated with factors related to diet, drugs and anthropometric measurements. We further demonstrate that microbiome data significantly improve the prediction accuracy for many human traits, such as glucose and obesity measures, compared to models that use only host genetic and environmental data. These results suggest that microbiome alterations aimed at improving clinical outcomes may be carried out across diverse genetic backgrounds.

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Acknowledgements

We thank the Segal and Elinav group members for discussions; J. Goodrich for sharing the processed twins microbiome data with us; and participants and staff of the LifeLines DEEP cohort for their collaboration. S.C. thanks the Abisch–Frenkel Foundation. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under awards 076113 and 085475. E.S. is supported by the Crown Human Genome Center; the Else Kroener Fresenius Foundation; D. L. Schwarz; J. N. Halpern; L. Steinberg; and grants funded by the European Research Council and the Israel Science Foundation. E.E. is supported by Y. and R. Ungar, the Gurwin Family Fund for Scientific Research, the Leona M. and Harry B. Helmsley Charitable Trust, the Israel Science Foundation and the Helmholtz Foundation. E.E. holds the Sir Marc and Lady Tania Feldmann Professorial Chair in Immunology, is a senior fellow of the Canadian Institute for Advanced Research, and is an international scholar at the Bill and Melinda Gates Foundation and Howard Hughes Medical Institute. D.R. received a Levi Eshkol PhD Scholarship for Personalized Medicine by the Israeli Ministry of Science. LLD was made possible by grants from the Top Institute Food and Nutrition (GH001) to C.W. C.W. is funded by a European Research Council (ERC) advanced grant (FP/2007-2013/ERC grant 2012-322698), a Netherlands Organization for Scientific Research (NWO) Spinoza prize (NWO SPI 92-266) and the Stiftelsen Kristian Gerhard Jebsen foundation (Norway). A.Z. holds a Rosalind Franklin Fellowship (University of Groningen), ERC starting grant (715772) and NWO Vidi grant (178.056). J.F. is funded by an NWO Vidi grant (NWO-VIDI 864.13.013). A.Z. and J.F. are also funded by CardioVasculair Onderzoek Nederland (CVON 2012-03).

Author information

Author notes

    • Daphna Rothschild
    • , Omer Weissbrod
    •  & Elad Barkan

    These authors contributed equally to this work.

    • Eran Elinav
    •  & Eran Segal

    These authors jointly supervised this work.

Affiliations

  1. Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel

    • Daphna Rothschild
    • , Omer Weissbrod
    • , Elad Barkan
    • , Tal Korem
    • , David Zeevi
    • , Paul I. Costea
    • , Anastasia Godneva
    • , Iris N. Kalka
    • , Noam Bar
    • , Smadar Shilo
    • , Dar Lador
    • , Noa Kosower
    • , Gal Malka
    • , Bat Chen Wolf
    • , Tali Avnit-Sagi
    • , Maya Lotan-Pompan
    • , Adina Weinberger
    •  & Eran Segal
  2. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel

    • Daphna Rothschild
    • , Omer Weissbrod
    • , Elad Barkan
    • , Tal Korem
    • , David Zeevi
    • , Paul I. Costea
    • , Anastasia Godneva
    • , Iris N. Kalka
    • , Noam Bar
    • , Smadar Shilo
    • , Dar Lador
    • , Noa Kosower
    • , Gal Malka
    • , Bat Chen Wolf
    • , Tali Avnit-Sagi
    • , Maya Lotan-Pompan
    • , Adina Weinberger
    •  & Eran Segal
  3. University of Groningen, University Medical Center Groningen, Department of Genetics, 9713 GZ Groningen, The Netherlands

    • Alexander Kurilshikov
    • , Arnau Vich Vila
    • , Jingyuan Fu
    • , Cisca Wijmenga
    •  & Alexandra Zhernakova
  4. University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, 9713 GZ Groningen, The Netherlands

    • Arnau Vich Vila
  5. Immunology Department, Weizmann Institute of Science, Rehovot 7610001, Israel

    • Niv Zmora
    • , Meirav Pevsner-Fischer
    •  & Eran Elinav
  6. Internal Medicine Department, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel

    • Niv Zmora
  7. Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel

    • Niv Zmora
    •  & Zamir Halpern
  8. Day Care Unit and the Laboratory of Imaging and Brain Stimulation, Kfar Shaul Hospital, Jerusalem Center for Mental Health, Jerusalem 9106000, Israel

    • David Israeli
  9. Digestive Center, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel

    • Zamir Halpern
  10. Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel

    • Shai Carmi
  11. University of Groningen, University Medical Center Groningen, Department of Pediatrics, 9713 GZ Groningen, The Netherlands

    • Jingyuan Fu
  12. Department of Immunology, K.G. Jebsen Coeliac Disease Research Centre, University of Oslo, 0424 Oslo, Norway

    • Cisca Wijmenga

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Contributions

D.R., O.W. and E.B. conceived the project, designed and conducted all analyses, interpreted the results, wrote the manuscript and are listed in random order. A.K., A.V.V., J.F., C.W. and A.Z. performed the analyses of the Dutch cohort and interpreted the results. T.K., D.Z. and A.W. designed protocols and supervised data collection. T.K., D.Z., P.I.C., A.G., I.N.K. and N.B. conducted microbiome analyses. S.S. and D.L. designed nutritional and drug databases. N.Z., M.P.-F, D.I. and Z.H. coordinated and supervised clinical aspects of data collection. N.K., G.M. and B.C.W. coordinated and designed data collection. T.A.-S., M.L.-P. and A.W. developed protocols and performed genotyping and microbiome sequencing. S.C. designed the genetic analyses. E.E. and E.S. conceived and directed the project and analyses, designed the analyses, interpreted the results and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Eran Elinav or Eran Segal.

Reviewer Information Nature thanks M. Georges and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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    Supplementary Information

    This file contains Power Simulations: A detailed description of our power simulations procedure and Statistical Aspects of the Microbiome-Association Index: A clarification regarding the assumptions behind the derivation of the microbiome-association index, and their statistical implications.

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    Supplementary Tables

    This file contains Supplementary Tables 1-28.

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DOI

https://doi.org/10.1038/nature25973

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